chr12-13980398-C-T

Variant names:

• chr12-13980398-C-T
• rs3764030
• NM_000834.5:c.-447-42G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001413995.1(GRIN2B):​c.-489G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 151,984 control chromosomes in the GnomAD database, including 3,318 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (3318 hom., cov: 32)
  • Exomes 𝑓: 0.14 (0 hom.)
• Consequence: GRIN2B NM_001413995.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.203
• Publications: 11 publications found

Genes affected

GRIN2B (HGNC:4586): (glutamate ionotropic receptor NMDA type subunit 2B) This gene encodes a member of the N-methyl-D-aspartate (NMDA) receptor family within the ionotropic glutamate receptor superfamily. The encoded protein is a subunit of the NMDA receptor ion channel which acts as an agonist binding site for glutamate. The NMDA receptors mediate a slow calcium-permeable component of excitatory synaptic transmission in the central nervous system. The NMDA receptors are heterotetramers of seven genetically encoded, differentially expressed subunits including NR1 (GRIN1), NR2 (GRIN2A, GRIN2B, GRIN2C, or GRIN2D) and NR3 (GRIN3A or GRIN3B). The early expression of this gene in development suggests a role in brain development, circuit formation, synaptic plasticity, and cellular migration and differentiation. Naturally occurring mutations within this gene are associated with neurodevelopmental disorders including autism spectrum disorder, attention deficit hyperactivity disorder, epilepsy, and schizophrenia. [provided by RefSeq, Aug 2017]

GRIN2B Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• developmental and epileptic encephalopathy, 27

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• intellectual disability, autosomal dominant 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000293563 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001413995.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2B	NM_000834.5	MANE Select	c.-447-42G>A		intron	N/A	NP_000825.2	Q13224
	GRIN2B	NM_001413995.1		c.-489G>A		5_prime_UTR	Exon 1 of 3	NP_001400924.1
	GRIN2B	NM_001413992.1		c.-447-42G>A		intron	N/A	NP_001400921.1	A0A8D9PHB2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2B	ENST00000609686.4	TSL:1 MANE Select	c.-447-42G>A		intron	N/A	ENSP00000477455.1	Q13224
	ENSG00000293563	ENST00000713643.1		c.35-46G>A		intron	N/A	ENSP00000518944.1	A0AAQ5BGK1
	GRIN2B	ENST00000630791.3	TSL:5	c.-447-42G>A		intron	N/A	ENSP00000486677.3	A0A0D9SFK0

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27098 AN: 151852 Hom.: 3318 Cov.: 32

Gnomad AFR AF: 0.0548

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.344

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.214

GnomAD4 exome AF: 0.143 AC: 2 AN: 14 Hom.: 0 Cov.: 0 AF XY: 0.143 AC XY: 2 AN XY: 14

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.167 AC: 2 AN: 12

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.178 AC: 27099 AN: 151970 Hom.: 3318 Cov.: 32 AF XY: 0.182 AC XY: 13492 AN XY: 74274

African (AFR) AF: 0.0547 AC: 2269 AN: 41474

American (AMR) AF: 0.380 AC: 5799 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 991 AN: 3470

East Asian (EAS) AF: 0.344 AC: 1763 AN: 5130

South Asian (SAS) AF: 0.262 AC: 1261 AN: 4810

European-Finnish (FIN) AF: 0.132 AC: 1398 AN: 10568

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.191 AC: 12956 AN: 67944

Other (OTH) AF: 0.216 AC: 454 AN: 2106

Alfa AF: 0.199 Hom.: 6863

Bravo AF: 0.194

Asia WGS AF: 0.287 AC: 997 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	16
DANN	Benign	0.92
PhyloP100		-0.20

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3764030; hg19: chr12-14133332;